4-1983991-T-G

Variant names:

• chr4-1983991-T-G
• NM_005663.5:c.1159A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005663.5(NELFA):​c.1159A>C​(p.Thr387Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T387M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NELFA NM_005663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.292

Genes affected

NELFA (HGNC:12768): (negative elongation factor complex member A) This gene is expressed ubiquitously with higher levels in fetal than in adult tissues. It encodes a protein sharing 93% sequence identity with the mouse protein. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene is mapped to the 165 kb WHS critical region, and may play a role in the phenotype of the WHS or Pitt-Rogers-Danks syndrome. The encoded protein is found to be capable of reacting with HLA-A2-restricted and tumor-specific cytotoxic T lymphocytes, suggesting a target for use in specific immunotherapy for a large number of cancer patients. This protein has also been shown to be a member of the NELF (negative elongation factor) protein complex that participates in the regulation of RNA polymerase II transcription elongation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056195587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NELFA	NM_005663.5	c.1159A>C	p.Thr387Pro	missense_variant	Exon 9 of 11	ENST00000382882.9	NP_005654.4
NELFA	XM_017008589.3	c.1243A>C	p.Thr415Pro	missense_variant	Exon 10 of 12		XP_016864078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NELFA	ENST00000382882.9	c.1159A>C	p.Thr387Pro	missense_variant	Exon 9 of 11	1	NM_005663.5	ENSP00000372335.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457648 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1192A>C (p.T398P) alteration is located in exon 9 (coding exon 9) of the NELFA gene. This alteration results from a A to C substitution at nucleotide position 1192, causing the threonine (T) at amino acid position 398 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.1
DANN	Benign	0.88
DEOGEN2	Benign	0.019	T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.43	.;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;.;N;N
REVEL	Benign	0.026
Sift	Benign	0.25	T;.;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.18
MutPred		0.21		.;.;Loss of phosphorylation at T387 (P = 0.0036);.;
MVP		0.12
MPC		0.24
ClinPred		0.068	T
GERP RS		-6.3
Varity_R		0.14
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-1985718;